an autodidact meets a dilettante…

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Posts Tagged ‘immune system

SARS-Cov2 and oxidative stress

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Dr Roger Seheult, just doing his job, workaholically

So I feel it’s time for me to get back to the epidemiology and immunology stuff that I know so little about, especially as it pertains to SARS-Cov2. Watching Dr Seheult’s Medcram updates again after a long hiatus, and catching up with them from the end of April, I note that he’s arguing – and I presume this is a mainstream view, as he clearly keeps an eye on the latest research – that the virus mostly does its damage in attacking the body’s endothelium, and that this in turn causes oxidative stress. The endothelium is a thin layer of cells, or a layer of thin cells, that form the inner lining of the blood and lymph vessels (one day I’ll find out what lymph actually is and does).

Oxidative stress is associated with an imbalance in the level of oxidants such as super-oxide anion and hydrogen peroxide, reduced forms of oxygen (with extra electrons). I don’t really understand this, so I’ll start from scratch. But just preliminary to that, the effects of oxidative stress are manifold. Here’s a summary from news-medical.net:

Oxidative stress leads to many pathophysiological conditions in the body. Some of these include neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, gene mutations and cancers, chronic fatigue syndrome, fragile X syndrome, heart and blood vessel disorders, atherosclerosis, heart failure, heart attack and inflammatory diseases.

It’s known that SARS-Cov2 enters via the lungs, and does damage there, but it’s now thought that most of the damage is done in the endothelium. To understand this, Dr Seheult is going to teach me some ‘basic’ stuff about metabolism, oxidation, energy production and such. So, we start with mitochondria, the energy-producing organelles inside our cells, which have their own DNA passed down the female line. Looking into a mitochondrion, we have the matrix inside, and around it, between the inner and outer membranes, is the inter-membrane space (IMS). Our food, broken down into its essential components, carbs, fats and proteins, is absorbed into the matrix, and somehow turned into ‘two-carbon units’ called acetyl coenzyme A. This is metabolism, apparently. These molecules go through a famous process called the Krebs cycle, of which I know nothing except that it’s about more metabolism… Although now I know that it produces electrons, tied up in two important molecules, NADH and FADH2. These electrons ‘love to be given up’, a way of saying they ‘want’ to be reduced. The molecule that gives up electrons is said to be oxidised, the receiving molecule is reduced. So think of a molecule being reduced as the opposite of losing, rather counter-intuitively. The oxidised molecule is the one that loses electrons. All this is about energy production within the matrix, and the aim is to end up with a molecule I’ve heard and forgotten much about, adenosine triphosphate (ATP). This molecule is the energy molecule, apparently, and the energy is produced by ‘knocking off’ one of the phosphates, according to Dr Seheult, leaving, apparently, adenosine diphosphate (ADP) plus ‘energy’ (clearly, this part needs a little more detail). So going from the diphosphate form to the triphosphate requires energy, going the other way releases energy – none of which really explains why ATP is the body’s energy source. Anyway…

Returning to the carbs, fats and proteins, they go through these mitochondrial processes to produce electrons which want to reduce stuff. So NADH goes to the membrane which separates the IMS from the matrix of the mitochondrion, where proteins can be found that are willing to accept electrons, i.e. to be reduced. The electrons are brought in ‘at the very top of the scale’ (?) and lose some of their reducing ability, so they go down to a lower state of reduction, and protons are pumped into the IMS. (I’m sure this is all true but making sense of it is another matter. It certainly makes me think of proton pump inhibitors, drugs that reduce gastric reflux, but that would be the subject of another set of posts). Then ‘it goes to another species’ by which I think Seheult means another protein, judging from the video, but what he means by ‘it’ I’ve no idea. The NADH? The wave/body of electrons? Anyway, things keep going down to a lower level, becoming more oxidised, and more and more protons are pumped out. So there comes to be a very high concentration of protons (H+) in the IMS, creating a very low PH (high acidity). Meanwhile, the electron transport chain has gone down so many levels that it can only reduce oxygen itself, which by accepting electrons turns finally into water. It’s apparently essential to have sufficient oxygen to keep this cycle going, and to keep the protons pumping, because the protons in the IMS want to move to a place of lower concentration, in the matrix. In doing this, they pass through a channel, which involves, somehow, a coupling of ADP to ATP. Without enough oxygen, this process is stymied, ATP can’t be supplied, leading to insufficient energy and cell death.

So, I think I understand this, as far as it goes. Now, if you over-eat, with lots of high-calorie fats and carbs entering the cells, you’ll likely end up with a surplus of electrons, tied up in NADH and FADH2, which can cause problems. This is where super-oxides come in.

Oxygen is the final electron acceptor in the electron transport chain, and when you add an electron to this final acceptor you get a super-oxide, an oxygen molecule with an additional electron, aka a radical. These are very reactive and dangerous. They can cause DNA damage and serious inflammation, and the body uses them to kill bacteria. If you add another electron, you get H2O2, hydrogen peroxide, and another one again produces a hydroxy radical, OH. Another electron gives water, so it’s these intermediate molecules that are called ‘dangerous species’. Cells such as neutrophils (a type of white blood cell) make these, via an enzyme called NADPH oxidase, as part of their defence against antigens, but an accumulation of these radicals is problematic and needs to be dealt with.

from Dr Seheult’s presentation, showing the production of reactive oxygen species (ROS) – super-oxide, hydrogen peroxide and hydroxy radicals

One enzyme the body uses to bring down these accumulating radicals is super-oxide dismutase (SOD), which takes two super-oxides and converts them into O2 and H2O2. SOD comes in three types, related to where they reside – in the mitochondria, the cytosol and the extracellular matrix. These enzymes are powered by zinc, copper and, in the mitochondria, manganese. So what happens to the extra hydrogen peroxide created? An enzyme called glutathione peroxidase (GPx) reduces H2O2 to water by giving it two electrons. Where do these electrons come from? According to Seheult, and this is presumably ‘basic’ microbiology, the antioxidant glutathione has two forms, oxidised and reduced. The reduced form is 2GS-H, with a hydrogen bonded to the sulphur group. The oxidised form is G-S-S-G, a disulphide bond replacing the hydrogen. With the reduced form, GPx donates its extra two electrons to H2O2, reducing it to water. The glutathione system is recharged by reducing it back with NADPH, which has two electrons which are converted to NADP+ (?) Glutathione reductase is the key enzyme in that process. It might take me a few lifetimes to get my head around just this much.

Meanwhile there’s another system… Catalase, an iron-boosted enzyme, can convert two molecules of H2O2 into O2 and H2O. This occurs in organelles called peroxisomes. The major point to remember in all this is that super-oxides are harmful species that can cause oxidative stress, and the major solutions come in the form of SOD and GPx. In fact the general name for these harmful molecules – super-oxides, hydrogen peroxide, and hydroxy radicals – is reactive oxygen species (ROS).

So we have to relate all this to the effects of SARS-Cov2, which enters the body through the ACE-2 (angiotensin-converting enzyme-2) receptor. According to a 2008 research paper, ACE-2, the receptor for which is blocked by SARS-Cov2, ‘confers endothelial protection and attenuates atherosclerosis’. Quoting from the paper, we find a section called ‘ACE-2 modulates ANG II(angiotensin 2)-induced ROS production in endothelial cells’. The researchers’ essential finding was that ‘ACE-2 functions to improve endothelial homeostasis’, and it seems this function is being disrupted by SARS-Cov2. As Dr Seheult puts it, SARS-Cov2 inhibits the inhibitor, that is it inhibits ACE-2, which normally acts to regulate angiotensin 1,7 (not explained in this particular video), thus allowing NADPH oxidase to keep producing super-oxides, with the resultant oxidative stress. As Seheult concludes here, subjects with compromised systems caused by diabetes, cardiovascular disease or obesity, affecting the production or effectiveness of SOD and GPx, might be relying on ACE-2 and angiotensin 1,7 to maintain some semblance of health. Are these the subjects that are succumbing most to the virus? That’s to be explored in future videos, and future posts here.

Reference

Coronavirus Pandemic Update 63: Is COVID-19 a Disease of the Endothelium (Blood Vessels and Clots)? (video by Dr Roger Seheult – clearly a hero in this time)


Written by stewart henderson

July 5, 2020 at 11:46 pm

Covid19: world progress, cytokine storms, our plans

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to be explored further

Canto: So while we need to be worried about – and to know something about – the cytokine storm that the Covid19 infection can lead to (and we’ll learn about that soon), there’s also a storm of activity on the SARS-CoV-2-fighting front.

Jacinta: Yes, intravenous zinc was talked about in the Medcram series as an effective tool in fighting viral pneumonia, and a world-first trial is being conducted by Austin Health and Melbourne University to test its effectiveness for Covid-19 sufferers with respiratory problems. We’re still catching up on the Medcram series, and update 52 talks of the drug ivermectin, already on the WHO list of essential medicines. The WHO website, incidentally, is promoting a ‘solidarity’ clinical trial for Covid-19 treatments, involving, singly or in combination, remdesivir, hydroxychloraquine, lopinavir, ritonavir and interferon beta-1a. So that gives some idea of the work that’s going on to fight symptoms and reduce the death rate.

Canto: And, you know, I’ve been feeling guilty about singling out the USA as the worst-case scenario all round. It’s not actually so. It’s not fair to look at total figures and point out that the USA tops the list for Covid19 fatalities, and draw calamitous conclusions. You have to take into account its much larger population compared, for example, to number two on the list, Spain. The US has suffered about 2.5 times the fatalities of Spain, but it has about 7 times the population. In fact, if you look at fatalities as a proportion of population, there are many countries worse off than the USA – namely Spain, Italy, France, the UK, Belgium (the worst hit), the Netherlands, Switzerland, Ireland and Sweden. All European countries, notably.

Jacinta: Yes and I’m sure they’ll all have their particular stories to tell about why this is happening to them, and will be wanting to learn lessons from Taiwan, Hong Kong, South Korea, and even our big faraway island, but I really want to look at solutions, in terms of eradicating the virus, or blocking it, or building up our immunity. Having said that, flattening the curve, and reducing fatalities, is a primary focus, which means continuing the physical distancing and looking for ways to keep economies running while this goes on. In spite of patches of civil libertarian activity here and there, the vast majority of our global population is on the same page with this, I think.

Canto: Well I’m looking at an Axios article from the Johns Hopkins website. It compares global performance under Covid19 to a mock pandemic exercise, Event 201, conducted some six months ago. They’ve found some positives and some negatives in their analysis. Positives – a greater degree of compliance with physical distancing measures than expected, ‘the degree of surge capacity augmentation in the health care system which has been possible’, and the rapid growth of international collaboration among scientists, leading to a quickened progress of trials for possible treatments. Negative – disparate and often contradictory messages from authorities – mostly political authorities – leading to confusion and distrust of governments and other institutions. This is partially explained by the complexity of the virus itself, which has made it difficult to characterise to the general public, and to be fully understood by non-medical authorities, such as political leaders.

Jacinta: It’s a weird situation, as there’s no end in sight, everyone’s worried about ending restrictions too soon, yet everyone’s worried about the economy, and those countries, like Australia, that are heading towards winter, are bracing for heightened problems, while northern hemisphere countries are hoping for summer’s relief but worried about the autumn when it might be hard to cope with a second outbreak, should it come. And medicos are warning that expectations of a vaccine in eighteen months might be overly optimistic. But I want to be optimistic – I want to look at anything that’ll reduce symptoms and save lives. One treatment, among many others it should be noted, is hydroxychloraquine, which is being given so much of a bad press, because of its being over-hyped by a Trump administration intent on getting political points for a silver-bullet cure. There have already been a number of small, less-than-gold-standard studies, some in which the drug is combined with the antibiotic azithromycin, and the results appear to be all over the place. We’re still awaiting the results of randomised, placebo-controlled, double-blinded studies, which are under way.

Canto: I note that a couple of reports on chloraquine and hydroxychloraquine on the JAMA website have been taken down, I suspect because of all the politicising. That’s a shame. Anyway I mentioned the cytokine storm at the beginning of this post, so I’ll try to comprehend it. A clue to the meaning comes in this mid-March article on the Lancet website. In an early sentence it mentions ‘cytokine storm syndrome’, and in the following sentence refers to the treatment of ‘hyperinflammation’. It seems the two terms are interchangeable. Another term, in the very next sentence, is ‘a fulminant and fatal hypercytokinaemia’….

Jacinta: Sounds like they’re just showing off.

Canto: Please don’t say that about our frontline covidtroops. Okay, a better site for understanding cytokines and their storms is this from New Scientist. As we’ve guessed, it’s an over-reaction of the immune system, sometimes fatal. Cytokines are small proteins, produced throughout the body, which trigger inflammation as an immune response. Sometimes the intensity of the cytokine response results in hyperinflammation. So you might say the cytokine storm is the cause and hyperinflammation the effect.

Jacinta: So this raises questions. For example, why do some have what seems an over-production of these cytokines and others don’t, in response to SARS-CoV-2 in particular? And what do these cytokines actually do to cause inflammation?

Canto: You’re asking me? Well, it’s conjectured that younger people don’t have the developed immune system that produces all these cytokines, and that’s why you don’t see symptoms. But that raises the question – do others have over-developed immune systems, but maybe only for this particular virus? Is there a general goldilocks level?

Jacinta: And is there a way of distinguishing between those who succumb to the hyperinflammation, which in turn can cause acute respiratory distress syndrome (ARDS), and those who succumb to the virus itself? Or is it always the immune response that does people in?

Canto: I don’t think so. If the immune response doesn’t work at all, I suspect the virus will spread like a cancer to the rest of the body?

Jacinta: That can’t be right. That’d mean those kids who don’t suffer the cytokine storm, or any immune reaction, would remain infected until it spread through their bodies and they dropped dead. That definitely isn’t happening.

Canto: No, you’re right – they’re developing antibodies, presumably, (and that’s a whole other story), without going through much in the way of suffering. In fact, children’s apparent immunity to the virus is something of a mystery that demands further research. If everyone could develop that kind of immunity…

Jacinta: So many questions we can’t answer. I mean, not just the myriad questions we, as dilettantes and autodidacts, can’t answer, but the fewer but many questions epidemiologists, virologists and ICU workers can’t answer. But I propose that we continue to try and educate ourselves and explore, in our feeble but earnest way. I propose that we dedicate this blog, for the foreseeable, to exploring terms and conditions, so to speak, and treatments, such as ‘cytokine’, ‘ACE-2’, ‘hypoxia’ and ‘quercetin’ and how they relate to or are affected by the Covid-19 infection. Like putting pieces together in a jigsaw puzzle, sort of. It might help us being overwhelmed by the whole picture.

Canto: Okay, let’s try it.

References

Coronavirus pandemic update 52, Medcram youtube video

https://coronavirus.jhu.edu/news

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext

https://www.newscientist.com/term/cytokine-storm/

https://www.centerforhealthsecurity.org/event201/

https://www.axios.com/coronavirus-global-pandemic-preparation-fdce4bff-f1d3-433d-bceb-cc20ac869102.html

https://jamanetwork.com/journals/jama/pages/coronavirus-alert

Written by stewart henderson

April 29, 2020 at 11:55 am

some thoughts on regression to the mean and what causes what

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Regression effects are ubiquitous, and so are misguided causal stories to explain them. Daniel Kahneman

Canto: So here’s an interesting thought, which in some ways is linked to the placebo effect and our attributing recovery from an illness to something we ate, drank or did, rather than to the silent and diligent work of our immune system. You know about the regression to the mean concept?

Jacinta: Of course. It’s a statistical phenomenon that we tend not to account for, because we’re always looking for or imagining causal effects when they don’t exist.

Canto: Well, they do exist but we attribute the wrong causal effects – we don’t account for ‘bad luck’, for example, which of course is caused, usually by factors we can’t easily uncover, so for convenience we give it that name. For example, a golfer might be said to have had an unlucky day with the putter because we observe that she she went incredibly close to dropping a number of difficult long putts, but none of them went in, so she made five over par instead of even. Of course every one of those failed putts was caused – one because her aim wasn’t quite true, another due to a tuft of grass, another because of a last moment gust of wind and so on… 

Jacinta: And some of those causes might be deemed unlucky, because on a less windy day, or with a better maintained green, those putts might’ve gone in.

Canto: Okay okay, there is such a thing as luck. But luck, I mean real luck, like the effect of a sudden gust of wind that nobody could’ve factored in, tends to even itself out, which is part of regression to the mean. But let me get back to illness. Take an everyday illness, like a cold, a mouth ulcer (which I suffered from recently)…

Jacinta: Or a bout of food poisoning, which I suffered from recently…

Canto: Yes, something from which we tend to recover after a few days. So the pattern of the illness goes something like this – Day 1, we’re fine. Day 2, we feel a bit off-colour. Day 3 we definitely feel much worse. Day 4, much the same. Day 5, starting to feel better. Day 6, definitely a lot better. Day 7, we’re fine. So it follows a nice little bit of a sine wave – two peaks and a trough – as shown above. 

Jacinta: So you’re saying that getting back up to the peak again is regression to the mean?

Canto: Well, sort of, but you’re getting ahead of me. Maybe it isn’t precisely, because a mean is the midpoint in a fluctuation between two extremes. Sort of. Anyway, let me explain. When you’re ill, you can choose to ride it out, or you can go to a doctor, or take some sort of medication, or some concoction recommended by a friend, or a reflexologist, whatever. But here’s the thing. You’re not likely to go to the doctor/acupuncturist/magus on day 2, when you’re just starting to feel queasy, you’re much more likely to go when you’re at the bottom of the trough, and then you’ll attribute your recovery to whatever treatment you’ve received, when it’s really more about regression to the mean. Sort of.

Jacinta: Hmmm. I agree that we’re unlikely to rush to the doctor or even the medicine cabinet when we’re just feeling a bit queasy, but that’s probably because experience tells us we’ll feel better soon – that maybe we’re already at the bottom of a little trough. But when we start going into a deeper trough, naturally we start getting worried – maybe it’s pneumonia, or tuberculosis…

Canto: Or diphtheria, malaria, typhoid, cholera, bubonic plague, acute myeloid leukaemia….

Jacinta: Don’t mock, I’ve had all of those. But it’s interesting to think of illness and wellness in this wave form. I’m not sure if it works as regression to the mean. Because wellness is just, well, feeling well. Feeling ‘normal’ or okay. We don’t tend to feel super-well – do we?

Canto: You mean you don’t believe in biorhythms? So you think the line pattern would be like, a straight horizontal one with a few little and big troughs here and there, and then finally off the cliff and straight down to death?

Jacinta: Well, no, isn’t it a slow decline into second childhood and mere oblivion – sans teeth, sans eyes, sans taste, sans everything?

Canto: Haha well not so much with modern medicine – though my hearing’s starting to go. But one of them-there invisible implants should fix that, at a price. But you’re probably right – what we call wellness at sixty is a lot different from the wellness we felt at twenty, but we’re probably lucky we can’t feel our way back to that twenty-something feeling. But getting back to the case of the person who applies a treatment and then gets better, there are, I suppose, three scenarios. The treatment caused the improvement, the treatment had no effect (the person improved for other reasons – such as our super-amazing immune system), or the treatment actually had a detrimental effect, but the person got better anyway, probably due to our wondrous immune system.

Jacinta: So that’s where the placebo idea comes in. And our tendency to over-determine for causality. You mention something like a cold, which is generally a viral infection, and mostly rhinoviral. The symptoms, like a runny nose and a sore throat, are actually caused by a mixture of the virus itself and the immune system fighting it, but mostly the latter….

Canto: Yeah, is that about antigens, or antibodies, I always get confused…

Jacinta: Well, it’s very very complicated, with T cells, immunoglobulin and whatnot, but essentially antigens are the baddies which trigger an antibody response, so antibodies are the goodies. So, if someone has a cold then unless they know their immune system is compromised in some way, the best thing is to let their immune system do its job, which might cause a few days’ discomfort, like extra phlegm production as the system, the antibodies or whatever, attempts to expel the invaders.

Canto: Yes, but the immune system is invisible to us, and is vastly under-estimated by many people, who tend to like to see something, like a big bright red pill, or a reflexology foot massage, or a bunch of needles needling their chi energy points, or unblocking their chakras…

Jacinta: Can they see their chakras?

Canto: No, but the magus can, with his various chakra-probing methods, and aural and oratorical senses developed over a lifetime – that’s why he’s a magus, dummy.

Jacinta: Yeah, and I’m sure we can all feel when our chakras are unblocked. It’s sort of like body plumbing.

Canto: So, getting back to reality, there is definitely something like this regression to the mean, to our own individual ‘normal’, but maybe ever-declining physical and mental state, that our wonderful immune system helps us to maintain, a system we rely on more than we realise….

Jacinta: Yes, but you know, it’s good that we don’t realise it so much, because think of all the acupuncturists, Alexander technicians, anthroposophicalists, antipharmaceuticalists, aromatherapists, auriculotherapists and ayurvedicists whose jobs might be on the line – and that’s just the A’s! Then we have the baineotherapist, the bead therapists and the bowen therapists, not to mention the chakra scalpel weaponmasters… can you imagine all those folk not being able to make a living?

Canto: Okay, that’s enough. It truly is a sad thing to think upon, but never fear, your horror scenario will never eventuate, my faith in human nature tells me….